Response to Infliximab in Crohn's Disease: Genetic Analysis Supporting Expression Profile.

Substantial proportion of Crohn's disease (CD) patients shows no response or a limited response to treatment with infliximab (IFX) and to identify biomarkers of response would be of great clinical and economic benefit. The expression profile of five genes (S100A8-S100A9, G0S2, TNFAIP6, and IL11) reportedly predicted response to IFX and we aimed at investigating their etiologic role through genetic association analysis. Patients with active CD (350) who received at least three induction doses of IFX were included and classified according to IFX response. A tagging strategy was used to select genetic polymorphisms that cover the variability present in the chromosomal regions encoding the identified genes with altered expression. Following genotyping, differences between responders and nonresponders to IFX were observed in haplotypes of the studied regions: S100A8-S100A9 (rs11205276* G/rs3014866* C/rs724781* C/rs3006488* A; P = 0.05); G0S2 (rs4844486* A/rs1473683* T; P = 0.15); TNFAIP6 (rs11677200* C/rs2342910* A/rs3755480* G/rs10432475* A; P = 0.10); and IL11 (rs1126760* C/rs1042506* G; P = 0.07). These differences were amplified in patients with colonic and ileocolonic location for all but the TNFAIP6 haplotype, which evidenced significant difference in ileal CD patients. Our results support the role of the reported expression signature as predictive of anti-TNF outcome in CD patients and suggest an etiological role of those top-five genes in the IFX response pathway.

Cancer testis antigen expression in gastrointestinal stromal tumors: new markers for early recurrence.

Cancer testis antigens (CTAs) are expressed in a variety of malignant tumors but not in any normal adult tissues except germ cells and occasionally placenta. Because of this tumor-associated pattern of expression, CTAs are regarded as potential vaccine targets. The expression of CTAs in gastrointestinal stromal tumors (GIST) has not been analyzed systematically previously. The present study was performed to analyze the expression of CTA in GIST and to determine if CTA expression correlates with prognosis. Thirty-five GIST patients were retrospectively analyzed for their expression of CTAs by immunohistochemistry using the following monoclonal antibodies (mAb/antigen): MA454/MAGE-A1, M3H67/MAGE-A3, 57B/MAGE-A4, CT7-33/MAGE-C1 and E978/NY-ESO-1. Fourteen tumors (40%) expressed 1 or more of the 5 CTAs tested. Fourteen percent (n = 5/35) were positive for MAGE-A1, MAGE-A3 or MAGE-A4, respectively. Twenty-six percent (n = 9/35) stained positive for MAGE-C1 and 20% (n = 7/35) for NY-ESO-1. A highly significant correlation between CTA expression and tumor recurrence risk was observed (71% vs. 29%; p = 0.027). In our study population, the high-risk GIST expressed CTAs more frequently than low-risk GIST (p = 0.012). High-risk GISTs which stained positive for at least 1 CTA, recurred in 100% (n = 25) of the cases. This is the first study analyzing CTA expression in GIST and its prognostic value for recurrence. The CTA staining could add information to the individual patient prognosis and represent an interesting target for future treatment strategies.

Douteurs thoraciques en médecine ambulatoire. Sans oublier les patients qui n'ont "rien au coeur" [Thoracic pain in primary care. Don't forget the patients without heart disease].

Thoracic pain in primary care. Don't forget the patients without heart disease Thoracic pain is a frequent medical complaint. Diagnostic and therapeutic guidelines have been developed and evaluated mostly in emergency and hospital settings. The primary care practitioner, as the emergency room doctor, has to identify quickly any severe condition needing urgent and highly specialized treatment. But in primary care, the process is not finished then! A patient with no vital and urgent problem still needs a diagnosis, information and adequate treatment. This review goes over the presentation of thoracic pain, the differential diagnoses and the challenge of treating such patients in ambulatory care.

Capsule endoscopy in the small bowel Crohn's disease.

CD is a chronic inflammatory disorder associated to mucosal and transmural inflammation of the bowel wall. It is well known that CD can affect the entire gastrointestinal. Therefore, ileocolonoscopy and biopsies of the terminal ileum as well as of each colonic segment to look for microscopic evidence of CD are the first-line procedures to establish the diagnosis. However, it has been observed that up to 30% of the patients have only small bowel involvement. Evaluation of the small bowel has been made with radiological procedures, barium radiography, and abdominal computed tomography or by ileocolonoscopy or enteroscopy, but they have many recognized limitations. CE is undoubtedly a very useful diagnostic tool proposed to observe small-bowel lesions undetectable by conventional endoscopy or radiologic studies. We review different studies that have been published reporting the use of CE in suspected and evaluation of the extension or the recurrence in CD and also its use in pediatric population and its complications.

Metastatic Crohn’s disease.

A 51 year old man presented to the department of Dermatology, Regional University Hospital of Málaga, Málaga, Spain, in May 2013, with remarkable lesions on the perineal, perianal and gluteal regions reaching the top of the lower limbs, which he had first noted two years earlier. The physical examination revealed large erythematous-brownish plaques with a granulomatous appearance, polypoid lesions and areas of ulceration. In addition, Mycobacterium tuberculosis culture and serum QuantiFERON® TB Gold were negative. The patient was diagnosed to have metastatic Crohn’s disease which is an uncommon complication of Crohn’s disease.

Liver, Gastrointestinal, and Cardiac Toxicity in Intermediate Hepatocellular Carcinoma Treated With PRECISION TACE With Drug-Eluting Beads: Results From the PRECISION V Randomized Trial.

OBJECTIVE. The purpose of our study was to evaluate hepatic, gastrointestinal, and cardiac toxicity after PRECISION transarterial chemoembolization (TACE) with drug-eluting beads (DEB) versus conventional TACE with doxorubicin in the treatment of intermediate-stage hepatocellular carcinoma (HCC).SUBJECTS AND METHODS. Two hundred twelve patients (185 men and 27 women; mean age, 67 years) were randomized to TACE with DEB or conventional TACE. The majority of patients (67% in both groups) presented in a more advanced stage. Safety was measured by rate of adverse events (Southwest Oncology Group criteria) and changes in laboratory parameters. Cardiotoxicity was assessed with left ventricular ejection fraction (LVEF) mainly on MRI or echocardiography.RESULTS. The mean maximum postchemoembolization alanine transaminase increase in the DEB group was 50% less than in the conventional TACE group (p < 0.001) and 41% less in respect to aspartate transaminase (p < 0.001). End-of-study values returned to approximately baseline levels but with greater variability in conventional TACE patients. Treatment-emergent adverse events in the hepatobiliary system organ class occurred in 16.1% of DEB group patients compared with 25% of conventional TACE patients. There were fewer liver toxicity events in the DEB group. There was a small but statistically significant difference in mean change from baseline in LVEF between the two groups of 4 percentage points for the conventional TACE group (95% CI, 0.71-7.3; p = 0.018).CONCLUSION. PRECISION TACE with DEB loaded with doxorubicin offers a safe therapy option for intermediate-stage HCC, even in patients with more advanced liver disease.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Obstructive fibrostenotic Crohn's disease.

Crohn's disease is often complicated by gastrointestinal strictures. Postoperative recurrence at the anastomotic site is common and repeated surgical interventions may be necessary. Medical treatment may relieve active inflammation (see chapter on active luminal disease) but fibrous strictures will not respond to this. Mechanical treatment methods consist of endoscopic balloon dilation, stricturoplasty or surgical resection. Fibrostenotic Crohn's disease does not respond to medical therapy and requires endoscopic or surgical treatment.

Maladie coeliaque: état des lieux [An update on celiac disease].

Celiac disease is a well-known entity in pediatrics and pediatric gastroenterology that is now also frequently encountered in the adult population. Apart from typical symptoms, celiac disease can present with a wide range of manifestations that are sometimes atypical, scarce or purely extraintestinal. Serologic and genetic testing are useful tools in case of low clinical probability in the early diagnostic algorithm. Upper gastrointestinal endoscopy remains the mainstay to confirm the diagnosis especially in atypical clinical presentations. Complications are rare but can be severe. Although gluten-free diet often leads to complete recovery, compliance is not universal and alternative treatment strategies are under investigation.

Fatal case of Epstein-Barr virus primo-infection, haemophagocytic syndrome in a 26-year-old patient treated with azathioprine for Crohn's disease: an autopsy case

Objective: A 26-year-old man with a history of Crohn's disease, treated with azathioprine since 2 years, presented an Epstein-Barr virus (EBV) primo-infection and exacerbation of digestive symptoms. Method: An ileo-colectomy was performed, which showed a fatal EBV lymphoproliferation disorder along with a haemophagocytic syndrome. EBV DNA load in the peripheral blood persisted to be high loaded during hospitalisation (479,000 copies per milliliter) despite triple antiviral treatment. Results: Autopsy revealed a systemic lymphoproliferation involving lymph nodes, gastrointestinal mucosa and solid viscera (heart, kidney, lungs, prostate, brain). This was compounded of a population of large polymorphic B cell, hypertrophic macrophages and T lymphocytes, associated to haemophagocytosis. These massive infiltrations mimicked macroscopically as ulcers in the intestinal mucosa and ranged from polymorphic with plasmocytic differentiation to monomorphic large cells. Autopsy results confirmed the absence of Crohn's disease reactivation. The EBV infection was observed in all organs within the large images of the B cell lymphoproliferations. Further postmortem investigations revealed a deficit of the azathioprine's metabolisation enzyme thiopurine methyltransferase (TPMT). Conclusion: We report and discuss herein the observations of a complete autopsy case along with the postmortem identification of the EBV infection type and TPMT mutation in a patient treated by azathioprine for Crohn's disease. Autopsy findings and further investigations helped explain the complicate clinical evolution and the fatal issue of the patient.

KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P&lt;0.0001) and the relative risk of death by 190% (P&lt;0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P&lt;0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.

Appropriateness of therapy for fistulizing Crohn's disease: findings from a national inflammatory bowel disease cohort.

BACKGROUND: About 30-50% of patients with Crohn's disease (CD) develop fistulae, implying significant disease burden and complicated clinical management. AIM: To assess appropriate use of therapy for fistulizing CD patients enrolled in the Swiss Inflammatory Bowel Disease Cohort using criteria developed by the European Panel on the Appropriateness of Crohn's disease Therapy. METHODS: Specific questionnaires were used to gather information on disease and its management. We assessed appropriateness of therapy at enrolment for adult CD patients with one or several fistulae. RESULTS: Two hundred and eighty-eight CD patients had fistulizing disease, of which 80% had complex fistulae and 32% currently had active draining fistulae. Mean age (s.d.) at diagnosis was 27 years (11), 51% males. Of the patients, 78% were judged as having globally an appropriate therapy, which was more often given for complex fistulae (87%) than for simple fistulae (67%). Antibiotics, azathioprine/MP, methotrexate and conservative surgery were almost always appropriate. Anti-tumor necrosis factor α was considered globally appropriate (91%), although most often with an uncertain indication. The 5ASA compounds, steroids and aggressive surgery were most often inappropriate (84%, 58% and 86% respectively). CONCLUSIONS: Formal appropriateness criteria for CD therapy were applied to a national cohort of IBD patients. For more than three-quarters of the patients with fistulizing CD, therapy was globally appropriate.

High altitude journeys and flights are associated with an increased risk of flares in inflammatory bowel disease patients.

BACKGROUND AND AIMS: Hypoxia can induce inflammation in the gastrointestinal tract. However, the impact of hypoxia on the course of inflammatory bowel disease (IBD) is poorly understood. We aimed to evaluate whether flights and/or journeys to regions lying at an altitude of >2000 m above the sea level are associated with flare-ups within 4 weeks of the trip. METHODS: IBD patients with at least one flare-up during a 12-month observation period were compared to a group of patients in remission. Both groups completed a questionnaire. RESULTS: A total of 103 IBD patients were included (43 with Crohn's disease (CD): mean age 39.3 ± 14.6 years; 60 with ulcerative colitis (UC): mean age 40.4 ± 15.1 years). Fifty-two patients with flare-ups were matched to 51 patients in remission. IBD patients experiencing flare-ups had more frequently undertaken flights and/or journeys to regions >2000 m above sea level within four weeks of the flare-up when compared to patients in remission (21/52 [40.4%] vs. 8/51 [15.7%], p=0.005). CONCLUSIONS: Journeys to high altitude regions and/or flights are a risk factor for IBD flare-ups occurring within 4 weeks of travel.

Patients' preferences on information and involvement in decision making for gastrointestinal surgery.

BACKGROUND: The relationship between physicians and patients has undergone important changes, and the current emancipation of patients has led to a real partnership in medical decision making. The present study aimed to assess patients' preferences on different aspects of decision making during treatment and potential complications, as well as the amount and type of preoperative information wanted before visceral surgery. METHODS: This was a prospective non-randomized study based on a questionnaire given to 253 consecutive patients scheduled for elective gastrointestinal surgery. RESULTS: In considering surgical complications or treatment in the intensive care unit, 64 % of patients wished to take an active role in any medical decisions. The respective figures for cardiac resuscitation and treatment limitations were 89 and 60 %. As for information, 73, 77, and 47 % of patients wish detailed information, information on a potential ICU hospitalization, and knowledge of cardiac resuscitation, respectively. Elderly and low-educated patients were significantly less interested in shared medical decision making (p = 0.003 and 0.015), and in receiving information (p = 0.03 and 0.05). Similarly, involvement of the family in decision making was significantly less important to elderly and male patients (p = 0.05 and 0.03, respectively). Neither the type of operation (minor or major) nor the severity of disease (malignancies versus non-malignancies) was a significant factor for shared decision making, information, or family involvement. CONCLUSIONS: The vast majority of surgical patients clearly want to get adequate preoperative information about their disease and the planned treatment. They also consider it crucial to be involved in any kind of decision making for treatment and complications. For most patients, the family role is limited to supporting the treating physicians if the patient is unable to participate in decision making.

Appropriateness of colonoscopy in Europe (EPAGE II). Chronic diarrhea and known inflammatory bowel disease.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for investigation of chronic diarrhea, management of patients with known inflammatory bowel disease (IBD), and for colorectal cancer (CRC) surveillance in such patients, and to report report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews, and primary studies regarding the evaluation of chronic diarrhea, the management of IBD, and colorectal cancer surveillance in IBD was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: According to the literature, colonoscopic evaluation may be justified for patients aged > 50 years with recent-onset chronic diarrhea or with alarm symptoms. Surveillance colonoscopy for CRC should be offered to all patients with extensive ulcerative colitis or colonic Crohn's disease of 8 years' duration, and to all patients with less extensive disease of 15 years' duration. Intervals for surveillance colonoscopy depend on duration of evolution, initial diagnosis, and histological findings. The EPAGE II criteria also confirmed the appropriateness of diagnostic colonoscopy for diarrhea of > 4 weeks' duration. They also suggest that, in addition to assessing extent of IBD by colonoscopy, further colonoscopic examination is appropriate in the face of persistent or worsening symptoms. Surveillance colonoscopy in IBD patients was generally appropriate after a lapse of 2 years. In the presence of dysplasia at previous colonoscopy, it was not only appropriate but necessary. CONCLUSIONS: Despite or perhaps because of the limitations of the available published studies, the panel-based EPAGE II (http://www.epage.ch) criteria can help guide appropriate colonoscopy use in the absence of strong evidence from the literature.